A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4

Terri H. Beaty, Jeffrey C. Murray, Mary L. Marazita, Ronald G. Munger, Ingo Ruczinski, Jacqueline B. Hetmanski, Kung Yee Liang, Tao Wu, Tanda Murray, M. Daniele Fallin, Richard A. Redett, Gerald Raymond, Holger Schwender, Sheng Chih Jin, Margaret E. Cooper, Martine Dunnwald, Maria A. Mansilla, Elizabeth Leslie, Stephen Bullard, Andrew C. LidralLina M. Moreno, Renato Menezes, Alexandre R. Vieira, Aline Petrin, Allen J. Wilcox, Rolv T. Lie, Ethylin W. Jabs, Yah Huei Wu-Chou, Philip K. Chen, Hong Wang, Xiaoqian Ye, Shangzhi Huang, Vincent Yeow, Samuel S. Chong, Sun Ha Jee, Bing Shi, Kaare Christensen, Mads Melbye, Kimberly F. Doheny, Elizabeth W. Pugh, Hua Ling, Eduardo E. Castilla, Andrew E. Czeizel, Lian Ma, L. Leigh Field, Lawrence Brody, Faith Pangilinan, James L. Mills, Anne M. Molloy, Peadar N. Kirke, James M. Scott, Mauricio Arcos-Burgos, Alan F. Scott

Research output: Contribution to journalArticlepeer-review

458 Scopus citations


Case-parent trios were used in a genome-wide association study of cleft lip with and without cleft palate. SNPs near two genes not previously associated with cleft lip with and without cleft palate (MAFB, most significant SNP rs13041247, with odds ratio (OR) per minor allele = 0.704, 95% CI 0.635-0.778, P = 1.44 × 10-11; and ABCA4, most significant SNP rs560426, with OR = 1.432, 95% CI 1.292-1.587, P = 5.01 × 10-12) and two previously identified regions (at chromosome 8q24 and IRF6) attained genome-wide significance. Stratifying trios into European and Asian ancestry groups revealed differences in statistical significance, although estimated effect sizes remained similar. Replication studies from several populations showed confirming evidence, with families of European ancestry giving stronger evidence for markers in 8q24, whereas Asian families showed stronger evidence for association with MAFB and ABCA4. Expression studies support a role for MAFB in palatal development.

Original languageEnglish (US)
Pages (from-to)525-529
Number of pages5
JournalNature Genetics
Issue number6
StatePublished - Jun 2010

Bibliographical note

Funding Information:
We sincerely thank all of the families at each recruitment site for participating in this study, and we gratefully acknowledge the invaluable assistance of clinical, field and laboratory staff who contributed to making this work possible. We are particularly grateful to K. Durda and J. L’Heureux of the University of Iowa for assistance with samples and phenotype data; L. Henkle for technical assistance; J. Resick, C. Brandon and K. Bardi of the University of Pittsburgh for assistance with recruitment; W. Carricato, K. Deeley and J. Ruff of the University of Pittsburgh for sample handling; P. Patel and M. Rose of Johns Hopkins for assistance with data analysis; F. Cheah of the National University of Singapore for sample processing and management; M. Feldkamp and J. Carey of the Utah Birth Defects Network for assistance with recruitment and case review; and D. Pearce of the Utah State University for sample collection and processing. Funding to support data collection, genotyping and analysis came from several sources, some to individual investigators and some to the consortium itself. The consortium for GWAS genotyping and analysis was supported by the National Institute for Dental and Craniofacial Research through U01-DE-018993; the International Consortium to Identify Genes and Interactions Controlling Oral Clefts, 2007–2009. This project was part of the Gene, Environment Association Studies Consortium (GENEVA) funded by the National Human Genome Research Institute (NHGRI) to enhance communication and collaboration among investigators conducting genome-wide studies for a variety of complex diseases. Our group benefited greatly from the work and efforts of the entire consortium, especially the work by the Coordinating Center (directed by B. Weir and C. Laurie of the University of Washington) in data cleaning and preparation of these case-parent trios for submission to the Database for Genotypes and Phenotypes (dbGaP). We also acknowledge the leadership of T. Manolio of NHGRI and E. Harris of National Institute of Dental and Craniofacial Research. Genotyping services were provided by the Center for Inherited Disease Research (CIDR), funded through a federal contract from the US National Institutes of Health (NIH) to Johns Hopkins University (contract number HHSN268200782096C). Funding for individual investigators and the replication studies include: R01-DE-014581 (T.H.B.); R37-DE08559 (J.C.M. and M.L.M.), R01-DE09886 (M.L.M., L.M. and L.L.F.), R01-DE012472 (M.L.M.), R01-DE014677 (A.C.L. and M.L.M.), R01-DE016148 (M.L.M.), P50-DE016215 (J.C.M. and M.L.M.), R21-DE016930 (M.L.M., E.E.C. and A.E.C.), R01-HD390661 and R01-DE016877 (R.G.M.). JK02-AEO15291 (A.C.L.), March of Dimes Basil O’Connor award #FY 98-0718 and Research Grant #6-FY01-61 (A.C.L.); NIH R03-AR-055313 and NIH P50-DE-16215 (project #3) (M.D.), K99-DE-018441 (R.M.); and the Canadian Institutes of Health Research MT-11263 (L.L.F.). The Smile Train Foundation supported data collection in Chengdu (E.W.J. and B.S.). This research was supported in part by the Intramural Research Program of the NIH National Institute of Environmental Health Sciences (A.J.W.).


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